机构:[1]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University Chengdu, China.四川大学华西医院[2]Guangdong Zhongsheng Pharmaceutical Co., Ltd. China.[3]Research Center for Public Health and Preventive Medicine, West China School of Public Health and Healthy Food Evaluation Research Center, NO. 4 West China Teaching Hospital, Sichuan University Chengdu, China.[4]Department of Gastrointestinal Surgery, West China Hospital, Sichuan University Chengdu, China.四川大学华西医院[5]Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University Chengdu, China.四川大学华西医院[6]Institute of Digestive Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University Chengdu, China.四川大学华西医院[7]School of Basic Medical Sciences, Chengdu Medical College Chengdu, China.
5T4, also named as trophoblast glycoprotein, is often upregulated in some cancer cells. Here, we demonstrated that 5T4 was highly expressed in gastric, colorectal, and pancreatic cancer, associated with significantly poor prognosis of gastrointestinal (GI) cancer patients. To search for new targeting drugs for GI cancer, we developed a novel anti-5T4 monoclonal antibody with high affinity and robust internalization ability and conjugated it to the potent microtubule inhibitor DM4 to produce conjugate H6-DM4. This antibody-drug conjugate (ADC) displayed significant cytotoxicity in a panel of GI cancer cell lines with IC50 values in the nanomolar range. H6-DM4 eradicated established GI tumor xenograft models at 2.5 mg/kg or 10 mg/kg without observable toxicity. Further, 5T4 was highly expressed in cancer-initiating cells (CICs) compared with non-CICs in colorectal cancer. In vitro and in vivo, treatment with H6-DM4 exhibited a powerful efficacy on colorectal CICs. Additionally, colorectal cancer cells resistant to platinum were effectively eliminated by H6-DM4. Taken together, our results showed 5T4-positive GI cancer cells, colorectal cancer-initiating cells, and platinum-resistant colorectal cancer cells were potently eliminated by H6-DM4, indicating H6-DM4 may be a potential candidate drug for GI cancer treatment.
基金:
This work is supported by National Major Scientific
and Technological Special Project [grant
number 2007ZX09302-010-005-003] and
National Natural Science Foundation of China
[grant numbers 81372822, 81501368 and
81672722]. The authors gratefully acknowledge
Prof. Xianming Mo for providing colorectal
CICs. The authors thank Prof. Feng Bi for
providing SW-480-Oxaliplatin and HCT116-Oxaliplatin
cell lines; Fan Yang (Jinkai biotechnol ogy company) for the mass spectrometric analysis;
Min Wu for improving this manuscript;
Hao Chen, Qiang Chen, and Dan Su for their
help in the experiments and data analysis.
Finally, the authors acknowledge technical expertise
of Yingbin Zhao for IHC.
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2018]版:
大类|2 区医学
小类|3 区肿瘤学
最新[2023]版:
大类|3 区医学
小类|3 区肿瘤学
第一作者:
第一作者机构:[1]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University Chengdu, China.[2]Guangdong Zhongsheng Pharmaceutical Co., Ltd. China.
共同第一作者:
通讯作者:
通讯机构:[1]State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University Chengdu, China.[2]Guangdong Zhongsheng Pharmaceutical Co., Ltd. China.[*1]State Key Laboratory of Biotherapy and Cancer Center/ Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 3-17 People Road, Chengdu 610041, China.
推荐引用方式(GB/T 7714):
Wang Ruixue,Lai Qinhuai,Tang Liangze,et al.A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models.[J].American journal of cancer research.2018,8(4):610-623.
APA:
Wang Ruixue,Lai Qinhuai,Tang Liangze,Tao Yiran,Yao Yuqin...&Yang Jinliang.(2018).A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models..American journal of cancer research,8,(4)
MLA:
Wang Ruixue,et al."A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models.".American journal of cancer research 8..4(2018):610-623